Histone deacetylase inhibitors induce apoptosis in human eosinophils and neutrophils

Abstract

BackgroundGranulocytes are important in the pathogenesis of several inflammatory diseases. Apoptosis is pivotal in the resolution of inflammation. Apoptosis in malignant cells is induced by histone deacetylase (HDAC) inhibitors, whereas HDAC inhibitors do not usually induce apoptosis in non-malignant cells. The aim of the present study was to explore the effects of HDAC inhibitors on apoptosis in human eosinophils and neutrophils.MethodsApoptosis was assessed by relative DNA fragmentation assay, annexin-V binding, and morphologic analysis. HDAC activity in nuclear extracts was measured with a nonisotopic assay. HDAC expression was measured by real-time PCR.ResultsA HDAC inhibitor Trichostatin A (TSA) induced apoptosis in the presence of survival-prolonging cytokines interleukin-5 and granulocyte-macrophage colony stimulating factor (GM-CSF) in eosinophils and neutrophils. TSA enhanced constitutive eosinophil and neutrophil apoptosis. Similar effects were seen with a structurally dissimilar HDAC inhibitor apicidin. TSA showed additive effect on the glucocorticoid-induced eosinophil apoptosis, but antagonized glucocorticoid-induced neutrophil survival. Eosinophils and neutrophils expressed all HDACs at the mRNA level except that HDAC5 and HDAC11 mRNA expression was very low in both cell types, HDAC8 mRNA was very low in neutrophils and HDAC9 mRNA low in eosinophils. TSA reduced eosinophil and neutrophil nuclear HDAC activities by ~50-60%, suggesting a non-histone target. However, TSA did not increase the acetylation of a non-histone target NF-κB p65. c-jun-N-terminal kinase and caspases 3 and 6 may be involved in the mechanism of TSA-induced apoptosis, whereas PI3-kinase and caspase 8 are not.ConclusionsHDAC inhibitors enhance apoptosis in human eosinophils and neutrophils in the absence and presence of survival-prolonging cytokines and glucocorticoids.

Effects of the Histone Deacetylase Inhibitor, Trichostatin A, in a Chronic Allergic Airways Disease Model in Mice

“…Numerous studies have shown that HDACi can promote the production of IL-5, which is a lifesupporting cytokine for eosinophils (Donnelly et al 2004). It has been suggested that the mechanism of HDACi effect on eosinophilia is induction of granulocyte apoptosis (Kankaanranta et al 2010). Recent experiments have shown that HDACi could induce apoptosis in human eosinophils and neutrophils in the absence and presence of survival-prolonging cytokines and glucocorticoids.…”

“…The activated GR could interact with specific transcription factors such as AP-1 and NF-jB and thus prevent the transcription of targeted inflammation genes. HDACi-induced loss of HDAC2 disrupts the association between GR and NF-jB (Kankaanranta et al 2010). In addition, in one study TSA was shown to enhance lipopolysaccharide-stimulated IL-8 and block attenuation of IL-8 transcription (Adcock et al 2007).…”

Caspase-3 and Caspase-6 cleave STAT1 in leukemic cells

“…Several studies show that HDACi modulate the acetylation of STAT1 and its transcriptional activity [30, 31]. The treatment of cells with HDACi alters protein degradation, signaling, gene expression, and apoptosis [32-34]. Accordingly, HDACi also are potent apoptosis inducers in certain cell types [28].…”

HDAC inhibitor therapy in autoimmunity and transplantation

“…First, HDACi may induce the apoptosis of cytokine-producing inflammatory cells,56 57 though there are relatively few data as yet for this mechanism of action using normal rather than transformed cells. Second, HDACi may disrupt the functional microtubule network in monocytes and thereby disrupt exocytotic release of cytokines from lysosomes 58.…”